The 2002-2003 pandemic of severe acute respiratory syndrome (SARS) posed an enormous threat to global public health and the social and economic stability. Its causative pathogen, the SARS-associated coronavirus (SARS-CoV), has been classified by NIAID as a Category C Priority Pathogen. SARS outbreaks remain a serious concern mainly due to possible zoonotic reintroduction of SARS-CoV into humans, accidental release from a laboratory or deliberate spreading of the virus by a bioterrorist attack. Therefore, an effective and safe vaccine is urgently needed for preventing future SARS outbreaks and for biodefense preparedness. We have identified a highly promising lead candidate vaccine antigen, the receptor binding domain (RBD) of the SARS- CoV spike (S) protein that contains the major neutralizing epitopes and can induce potent neutralizing antibody response and protection in animals against SARS-CoV infection. To rapidly translate our initial proof of concept findings into a solid platform of clinical trials, a consortium of experts was put together consisting of scientists from Baylor College Medicine, the new home of Sabin Vaccine Institute's product development partnership (BCM-Sabin), the New York Blood Center (NYBC) and the University of Texas Medical Branch (UTMB), and in partnership with industrial partners and non-profit organizations. The specific aims of this application are: (1) Expression, purification and pre-clinical characterization of the recombinant RBD (rRBD) protein as a vaccine candidate. The rRBD protein will be expressed in bacteria and yeast expression systems and one of these expression systems will be selected for subsequent studies based on yields, purity, stability, antigenicity, functionality, immunogenicity, and efficacy of the rRBD protein. The immunization regimens will be optimized and the ability of rRBD protein to induce cross-neutralizing antibody response, cross-protection and long-term immune responses and protection will be assessed. (2) Process development, characterization, formulation and stability profiling. A scalable and reproducible fermentation process for rRBD (10 liter scale) and a purification process using chromatographic technologies will be developed. Reproducibility will be confirmed. The specific product quality assays and vaccine formulations with alum and/or glucopyrranosyl lipid A (GLA), an innate adjuvant, will be developed. These assays and procedures will serve the basis for formal lot release and stability evaluation post-manufacturing. (3) Technology transfer, cGMP Manufacture, GLP toxicology and IND Preparation. The cell bank production, production processes and the formulation technology for the rRBD-based SARS vaccine will be transferred to Walter Reed Army Institute of Research (WRAIR) pilot facility for 60-L scale GMP manufacture, formulation and fill and finish. The clinical lots will be released by Sabin- Texas and following a pre-IND meeting with the U.S. FDA, GLP toxicology will be initiated at Frontier Biosciences, a Maryland-based contractor. PUBLIC HEALTH RELEVANCE: SARS-CoV is the first new human infectious disease agent of this century classified by NIAID as a Category C Priority Pathogen, and SARS outbreaks still remain a serious global concern mainly due to possible zoonotic reintroduction of SARS-CoV into humans or accidental release from a laboratory or deliberate spreading of the virus by a bioterrorist. We have identified a highly promising lead candidate vaccine antigen, the receptor binding domain (RBD) of the SARS-CoV spike (S) protein that can induce potent neutralizing antibody response and protection against SARS-CoV infection. Our objective is to develop a highly effective and safe recombinant RBD-based SARS vaccine that can be used in humans for prevention of future SARS outbreak and for biodefense preparedness.